Grant: Master's Award: Canada Graduate Scholarships

Major depressive disorder is the leading cause of disability worldwide, and 50% of those diagnosed do not respond adequately to first-line treatment. Currently, the most prominently prescribed antidepressants have undesirable side-effects and a lengthy delay in therapeutic response. There is a pressing need for faster, more effective pharmacological alternatives. Ketamine has recently been shown to have rapid and sustained antidepressant effects following a single dosage. The mammalian target of rapamycin (mTOR) pathway, which is essential for ketamines antidepressant effects, may mediated by the glycoprotein reelin. Alterations in reelin expression is seen in mood and psychotic disorders, suggesting that reelin down-regulation may be involved in the pathophysiology of depression. To assess the fast-acting antidepressant effects of reelin and ketamine, I will examine behavioural and neurobiological changes within a 24-hour period following drug administration. In animal models, depression-like symptoms will be induced through daily injections of the stress hormone corticosterone. I will then analyze the mechanisms and speed by which ketamine and reelin rescue these deficits. Behavioural effects will be analyzed using robust tests for anhedonia and learned helplessness (the forced swim test and latency for reward). Neurobiological changes will be analyzed using synaptoneurosomes, which allow the isolation of synaptic terminals, from the hippocampus. Serotonin transporter clustering will be analyzed on peripheral lymphocytes as an indicator of therapeutic response. This research could help us gain essential knowledge in the cellular roles underlying the pathophysiology of depression and could contribute to the development of more effective antidepressant drugs.